tbuckley/cabot-search huggingface dataset:
Immunotherapy-related toxicities: A retrospective analysis of barriers to prompt detection and initiation of treatment in renal cell carcinoma.
Authors: Daniel Zeter, Ina J Patel
Journal: Journal of Clinical Oncology (2023)

e16547 Background: In 2021, there was an estimated 76,000 patients diagnosed with kidney cancer in the United States, and 90% of these patients were diagnosed with renal cell carcinoma (RCC). The current treatment for RCC is the use of immune checkpoint inhibitors (ICIs), which allow the body to naturally fight against cancer cells without impedance. A common side effect of this therapy, however, is immunotherapy-related adverse events (irAE), which are toxicities where the bodies overactive immune system attacks noncancerous organs. When irAEs arise, the patient’s immunotherapy is stopped, and a steroid regiment is begun to dampen the immune system before re-starting immunotherapy. Time is crucial when treating irAEs, and this study is aimed to identify barriers in the onset of steroid treatment and identify interventions that can help providers and patients identify toxicities and begin steroid treatment as soon as possible. Methods: We conducted a retrospective study analyzing adult patients (ages 18-75) being treated for RCC at UT Southwestern Medical Center and Moncrief Cancer Institute (MCI). We specifically looked at patients being treated with ipilimumab, nivolumab, and pembrolizumab. The first portion included a chart review to identify patients and identify barriers to prompt treatment, i.e. fear of worsening hyperglycemia in diabetics, access to healthcare, delay of re-initiating immunotherapy. The second portion of this study will be to identify and test a possible intervention for these patients to ensure timely recognition of toxicities and prompt initiation of steroids. Results: Upon review of 201 patients with RCC stage III/IV, the most common toxicity found was colitis (28.4%), followed by transaminitis (9.0%) and pneumonitis (9.0%). The most common method for identification of toxicities was routine lab work performed before immunotherapy administration (30.4%), check-ins at regularly scheduled appointments (21.7%), and after-hour physician telephone lines (19.6%). Additionally, the average time from irAE identification to steroid administration was 1.45 days. Excluding toxicities found either at office appointments or on routine lab work, the average time to steroids from identification was 3.55 days. Our data collection also demonstrated that routine labs were the most likely factor to identify immunotherapy toxicity in a timely manner. Conclusions: Continuation of current practices can lead to further decreases in time to steroid treatment. This study can be used as a blueprint and expanded to further investigate irAEs in other solid tumors as well as contribute to management of the ever-evolving immunotherapy landscape.
Blood-based molecular profiling of Chinese patients with advanced renal cell carcinoma.
Authors: Xiaodong Fan, Mingwei Li, Xiaoxue Ma, Jiayue Qin, Shanbo Cao
Journal: Journal of Clinical Oncology (2023)

e16550 Background: The therapeutic landscape of renal cell carcinoma (RCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy in real time. Next-generation sequencing (NGS)-based profiling of circulating tumor DNA (ctDNA) shows promise for noninvasive detection. To evaluate the clinical utility of ctDNA analysis in RCC, we aimed to analyze the molecular characteristics of RCC using ctDNA by NGS. Methods: A total of 189 plasma samples and 26 matched tumor tissues from Chinese patients with advanced renal cell carcinoma (n = 189) were analyzed by Acornmed panel with 808 cancer-related genes, and matched white blood cell as germline comparators. Results: Overall, 29 germline mutations were detected in 14.3% (27/189) patients, such as TSC2 (5/189, 2.65%), FH (3/189, 1.6%) and VHL (2/189, 1.1%), of which 10 germline aberrations in DNA damage repair (DDR) genes were detected in 5.3% patients (10/18). In addition, a total of 1590 somatic variations were identified in 96.8% (183/189) ctDNA, including 1278 nonsynonymous single nucleotide variants, 126 small insertions or deletions, 75 copy number variations. And the median blood tumor mutation burden (bTMB) was 4.36 mut/Mb. Mutations in VHL (36/189, 19.4%) were the most prominent variation, followed by those in TP53 (19/189, 10.0%), BAP1 (12/189, 6.3%), PBRM1 (10/189, 5.3%) and SETD2 (7/189, 3.7%). Moreover, totals of 154 clinically actionable mutations from 92 patients (48.7%) were identified. In 26 patients with both tumor tissues and plasma samples, sequencing detected alterations in 100% (26/26) tumor tissue DNA (tDNA) and 96.2% (25/26) ctDNA, respectively. Furthermore, 29.6% of mutations of tissues were founded in ctDNA, and 21.6% of mutations of ctDNA were detected in tissues. Among them, 73.1% (19/26) patients had at least one overlapping variant called by tDNA and ctDNA. The most common shared mutation was VHL (5/26, 19.2%). Meanwhile, four shared copy number variants were detected in two patients (15.4%). Conclusions: Our study contributes to understand the molecular characteristics of RCC using ctDNA, which is a viable option for tissue when tissue is difficult to obtain. Furthermore, ctDNA testing by NGS is helpful for drug selection and provides more effective treatment options for RCC, particularly for hereditary RCC.
A randomized, open-label, phase II study of high-dose interleukin 2 vs high-dose interleukin 2 plus entinostat in renal cell carcinoma.
Authors: Roberto Pili, David I. Quinn, Ralph J. Hauke, Timothy Kuzel, Yan Han, Nabil Adra, Theodore F. Logan
Journal: Journal of Clinical Oncology (2023)

e16540 Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies such as high dose interleukin 2 (HD-IL2). We previously reported that the histone deacetylase (HDAC) inhibitor entinostat has antitumor effects in combination with HD-IL2 by decreasing Tregs function in a preclinical model of kidney cancer. Based on these preliminary data, we hypothesized that HDAC inhibition may enhance or resensitize patients (pts) with clear cell renal cell carcinoma (ccRCC) to HD-IL2. Our group has previously conducted a Phase II, single arm, clinical trial of entinostat in combination with HD-IL2 in ccRCC, which showed an objective response rate (ORR) of 37% and a median progression-free survival (mPFS) of 13.6 months as compared to historical data with single agent HD-IL2 of 20-25% and 4.2 months, respectively. Thus, we designed a multi-center, randomized, open label Phase II study with entinostat in combination with HD-IL2 in ccRCC patients. Methods: The primary objective was to estimate and compare PFS in pts randomized to receive either HD-IL2 plus entinostat (Arm 1) or HD-IL2 (Arm 2) and stratified by no prior therapies vs prior therapies. Due to unforeseen circumstances, enrollment halted after the first 10 patients. The treatment schedule was HD-IL2 600,000 units/kg administered IV every 8 hrs on Days 1-5 and Days 15-19 (maximum 28 doses) +/- entinostat 5 mg orally given every 2 weeks starting on Day-14, continuously. The study was originally designed to detect a 100% improvement of median PFS to 8.4 months in ARM 1. A one-sided stratified log-rank test with an overall sample size of 46 subjects (23 per group) achieves 80% power at a 0.10 significance level to detect a hazard ratio of 0.5 (median PFS of 4.2 months vs 8.4 months). Results: 10 pts (6 pts in Arm 1 and 4 pts in Arm 2) were enrolled. Among the 10 pts, only one had prior therapy (Arm 1). The most common treatment-related toxicities ( &gt; 50%, any grade) were diarrhea, hypotension, nausea, hypomagnesemia, hypophosphatemia, pruritus, hypocalcemia and thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. The most common ≥ grade 3 toxicities were hypotension (80%), hypophosphatemia (70%), and thrombocytopenia (60%). Two pts (33%: CI 4.3%-77.7%) achieved a partial response in Arm 1 and no pts in Arm 2. The median PFS was 12.4 months (CI 2.3-NE) in Arm 1 (13.3 months in pts with no prior therapies) and 2.8 months (CI 1.2-3.3) in Arm 2 (Logrank p-value 0.0167). We have collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study confirm that the combination of entinostat and HD-IL2 may be more active than HD-IL2 alone in pts with ccRCC. Clinical trial information: NCT03501381 .
Prostate-specific antigen value at 3 &amp; 7 months (PSA-3mo, PSA-7mo) and overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation (ADT) with or without orteronel (SWOG S1216).
Authors: Mamta Parikh, Catherine Tangen, Maha H. A. Hussain, Shilpa Gupta, Yeonjung Jo, Andrea Harzstark, Channing Judith Paller, Saby George, Matthew R. Zibelman, Heather H. Cheng, Benjamin L. Maughan, Jingsong Zhang, Russell Kent Pachynski, Alan Haruo Bryce, Daniel W. Lin, David I. Quinn, Ian M Thompson, Tanya B. Dorff, Primo N Lara, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2023)

5074 Background: Analysis of phase 3 studies of patients (pts) with mHSPC in the era of ADT, including in combination with docetaxel and/or androgen receptor axis targeted therapies have established PSA-7mo as a key prognostic marker. Our objective was to evaluate the association between PSA-3mo, PSA 7-mo and OS measured in the phase 3 S1216 trial in mHSPC comparing ADT + orteronel (treatment arm) vs ADT + bicalutamide (control arm) [NCT01809691]. Methods: Pts enrolled in the S1216 trial with available PSA-3mo &amp; PSA-7mo were included in this analysis. PSA responses were defined as complete response (CR) if PSA ≤ 0.2 ng/mL, partial response (PR) for PSA &gt;0.2 and ≤ 4ng/mL, and no response (NR) as PSA &gt;4 ng/mL at month 3 or 7. Landmark OS was measured and Cox regression model applied adjusting for stratification (performance status, extent of disease, early vs late start of treatment, treatment arm). Results: 1251 pts were alive and evaluable for PSA-3mo and 1231 pts were evaluable at 7 mo, out of a total of 1279 pts. The median age was 67 (range: 43-92), 10% of patients were black, 96% had a Zubrod performance status of 0-1. Median PSA at baseline was 29 ng/ml (range: 2-6710). Of pts on treatment vs.control arm, PSA-3mo CR, PR, and NR occurred in 52% vs 35%; 31% vs 42%, and 17% vs 23%, respectively. Of pts on treatment vs control arm, PSA-7mo CR, PR, and NR occurred in 61% vs 46%, 20% vs 26%, and 19% vs 29%, respectively. CR or PR at either timepoint led to significantly better outcomes than those with NR. No interaction between treatment arm and PSA response was observed in terms of OS. Conclusions: PSA-3mo and PSA-7mo are strong prognostic markers for pts with mHSPC. More pts on ADT with orteronel achieved CR at 3 and 7 mo. In addition to its use in counseling patients in the clinic, PSA-3mo and PSA-7mo may be used as parameters for designing future trials in pts with mHSPC, utilizing the next generation of intensification or de-intensification treatment regimens. Clinical trial information: NCT01809691 . [Table: see text]
The same outcome of cancer patients treated with radiotherapy or chemoradiotherapy regardless COVID-19 status.
Authors: Zhenyu Zhang, Ping Li, Juan Zhou, Qinghai Lin, Xun Peng, Xue Meng, Man Hu, Miaoqing Zhao, Kun Ru
Journal: Journal of Clinical Oncology (2023)

e18866 Background: COVID-19 has spread all over the world and infects people including cancer patients. The aim of this study is to explore the influence of COVID-19 infection on various cancer patients in China. Methods: A total of 167 cancer patients receiving radiotherapy or chemoradiotherapy from July 2022 to February 2023 were included in this study. Tumor types included lung, breast, esophageal, nasopharyngeal, cervical, pancreatic, thymus, rectal, bladder, testicular cancers, and glioblastoma, etc. The patients were divided into three groups: no COVID-19 infection during the therapy cycle (group A, n = 52), therapy beginning at least 10 days after the first positive COVID-19 tests (group B, n = 43), and therapy beginning less than 10 days after the first positive COVID-19 tests (group C, n = 72). The COVID-19 variants in this study were BA5.5.6, BA.5.2, and BF.7. Results: Some infection-related parameters were increased in COVID-19 positive cancer patients, such as SAA (group A vs group B, p= 0.0006; group A vs group C, p= 0.0004), hsCRP (group A vs group B, p= 0.0043; group A vs group C, p= 0.0144), ferritin (group A vs group B, p= 0.0417; group A vs group C, p= 0.0319) and PA (group A vs group C, p= 0.011), yet IL-6 and PCT were of no difference among three groups. Similarly, the serum markers for the myocardial and hepatic lesions, such as LDH (group A vs group B, p= 0.0064; group A vs group C, p= 0.0369), HBDH (group A vs group B, p= 0.0116; group A vs group C, p= 0.0414), and CHE (group A vs group B, p= 0.0303; group A vs group C, p= 0.0256), were raised in both group B and group C, but AST, CK, CK-MB, ADA, GGT, cTnT, and proBNP showed no difference between COVID-19 positive and negative cancer patients. The cancer patients receiving radiotherapy or chemoradiotherapy showed no differences in the lowest WBC, Hgb, platelets, NLR (Neutrophil to Lymphocyte Ratio), and lymphocyte subtype counts among three groups. Nevertheless, the leukopenia was apparent in group C (group A vs group C, p= 0.0031; group B vs group C, p= 0.0194), and no obvious difference between group A and group B. Finally, the dropout rates in three groups were nearly the same (group A, 4/52; group B, 6/43; group C, 6/72), and the causes of treatment interruption varied, including pneumonia, deep venous thrombosis, mucosal damage, headache, diarrhea, agranulocytosis, esophageal fistula, etc. Moreover, the completion rate of treatment was not affected by the radiation dose or antitumor drugs in COVID-19 infected cancer patients. Conclusions: This study found that COVID-19 infection did not change the completion rate of radiotherapy or chemoradiotherapy in cancer patients, although some hematological and serum parameters altered during the treatment and infection. In contrast to NCCN guidelines, cancer patients positive for COVID-19 could be treated safely by radiotherapy or chemoradiotherapy.
The combination of APR-246 and carboplatin in olaparib-resistant high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC) cell lines.
Authors: Jose Alejandro Perez-Fidalgo, Juan Jose Martinez Pretel, Paloma Sanchez Serrano, Victoria Heredia, Marta Mendiola, Andres Redondo, Lidia Gonzalez Villena, Miriam Ruiz Linuesa, Begona Pineda
Journal: Journal of Clinical Oncology (2023)

e17504 Background: PARP inhibitors (PARPi), as Olaparib (OLA), have changed the therapeutic landscape in HGSOC and TNBC. However, most patients will develop resistance to PARPi. Although resistance mechanisms are poorly understood, it is suggested that BRCA mutations reversions or cell cycle alterations could be involved. APR-246 is a new targeted agent that restores p53 in TP53-mutated cells. The aim of our study was to assess the potential synergism of the combination of carboplatin (carbo) plus APR-246 in both OLA-sensitive and OLA-resistant HGSOC and TNBC cell lines. Methods: We selected two HGSOC (PEO1-S and Kuramochi-S) and one TNBC TP53 mutant cell lines (MDA-MB-231-S). Resistance to OLA was generated by pulse doses with IC75 OLA for 24 hours and recovered for two weeks during a period of 6 months (PEO1-R) and to increased concentrations of OLA for 72 hours during a period of 1 year (Kuramochi-R, MDA-MB-231-R). Next-generation sequencing was performed in order to assess mutations. IC50 of APR-246 and Carbo and the combination of both (combo) were calculated for Kura-S/R, PEO1-S/R and 231-S/R cell lines. Synergism between both drugs was assessed with Chou-Talalay method for combination index (CI) at Fa50. DNA damage was assessed by gamma-H2AX expression by western-blot (WB). Results: 231-S harboured a TP53 mutation (mut) (missense R280K) and BRCA wildtype (wt), in PEO1-S BRCA2 mut p.Y1655* and TP53 mut was detectable. Kuramochi-S was TP53 mut (missense D816Y) and BRCA2 mut. BRCA and p53 mutation remained unchanged in the resistant lines generated.The mutation profile of each line and the IC50 of APR-246, carbo and combo are shown in the table. IC50 of carboplatin is superior in all 3 resistant cell lines when compared to their sensitive parental line, suggesting a potential cross-resistance to platinum in OLA-resistance. The combination of carbo and APR-246 is synergistic even in OLA-resistant cell lines, in fact in those cross-resistant lines values of synergism by Chou-Talalay are improved by the combo suggesting a potential role of this combination in PARPi resistant cell lines. WB showed an increased DNA damage with the combo when compared to either single agent, with an increase in H2AX in all lines either sensitive or resistant. Conclusions: The combination of APR246 and carboplatin is synergistic in all 3 studied cell lines but also in the OLA resistant ones. The combo increased its synergistic effect suggesting a potential role of combo in OLA-resistant tumors. [Table: see text]
A multi-institutional prospective cohort study of minimal residual disease in peripheral T-cell lymphoma: Impact of autologous stem cell transplant.
Authors: Nicole C. Foley, David Russler-Germain, Marcus Watkins, Eric D. Jacobsen, Alison J. Moskowitz, Amanda F. Cashen, Todd A. Fehniger, Brad S. Kahl, Armin Ghobadi, Beth Reagan, Anne Fischer, Fei Wan, Austin Jacobsen, Karina Elias, Matt Holman, Natalie Hill, Skyler Gordon, Ying Huang, Steven M. Horwitz, Neha Mehta-Shah
Journal: Journal of Clinical Oncology (2023)

7563 Background: Roughly 80% of pts with peripheral T-cell lymphomas (PTCL) respond to CHOP-based therapy but 5-yr survival ranges between 20-40%. The high relapse rate after complete response (CR) suggests more sensitive response assessment, such as minimal residual disease (MRD) testing, could have prognostic or predictive value. Next generation sequencing (NGS) of the T-cell receptor (TCR) can detect a known TCR clonotype at 10 -5 . In a prospective study, we evaluated the utility of MRD testing via TCR NGS in PTCL (NCT03297697). Here we report results for pts pre- and post-autologous stem cell transplant (ASCT). Methods: This investigator-initiated, multi-institutional, prospective cohort study assessed MRD testing by TCR NGS in PTCL. Pts with previously untreated PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), PTCL with T-follicular helper (TFH) phenotype, or monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) treated with anthracycline-based curative-intent therapy were eligible. Baseline TCR (TRG or TRB) clonotypes were established from diagnostic tissue or peripheral blood if tissue was not available. TCR clonality was determined positive via the LymphoTrack TRG/TRB Assays – MiSeq (Invivoscribe, San Diego, CA) when top % reads were ≥2.5% and ≥2x above background. Samples were obtained at diagnosis (pre-treatment), following induction therapy (EOT/pre-ASCT), and serially post-ASCT. Results: Of 43 enrolled pts, 19 underwent consolidative ASCT, of which 10 had post-ASCT samples available for MRD testing (Table). Median age at ASCT was 62 years (range: 38-77). Baseline TCR clonotypes were identified in 10/10 pts. At pre-ASCT evaluation, 7/10 pts had detectable TCR MRD (‘pos’) and 3/10 pts had TCR MRD below the level of detection (‘neg‘). Of the 3 MRD neg pts pre-ASCT, 2 had CR and 1 had PR by PET-CT. All 7 TCR MRD pos pts pre-ASCT had CR by PET-CT. Of 7 MRD pos pts pre-ASCT, 6 remained MRD pos and 1 became MRD neg post-ASCT. Of the 4 MRD neg pts post-ASCT, none have relapsed at 52, 31, 34, and 31 mo post-ASCT. Of 7 MRD pos pts pre-ASCT, 3 have relapsed following ASCT (at 3, 9, and 29 mo post-ASCT). Conclusions: In this cohort of patients with PTCL receiving consolidative ASCT in CR1, all 4 pts with negative TCR MRD post-ASCT remain in remission at median follow up of 32.5 mo post-ASCT. The negative predictive value of TCR NGS MRD post-ASCT should be further evaluated. Clinical trial information: NCT03297697 . [Table: see text]
tRNA-derived fragments (tRFs) as regulators of oncogenes and tumor suppressor genes in head and neck squamous cell carcinoma.
Authors: Matthew Uzelac, Daniel John, Jaideep Chakladar, Wei Tse Li, Weg M. Ongkeko
Journal: Journal of Clinical Oncology (2023)

e18082 Background: Roughly 50,000 individuals are diagnosed with head and neck cancers in the United States yearly. Though risk factors and common therapeutic strategies are well-established, early detection of head and neck cancers remains challenging. One strategy for early detection is high-throughput analysis of both coding and noncoding RNA transcripts, which has become increasing implicated in cancer pathogenesis. One such noncoding transcript is tRNA-derived fragments (tRFs), which are the products of enzymatic cleavage of precursor tRNAs. Though tRFs have been suggested to play important roles in the regulation of mRNA translation (similar to other noncoding RNAs), their utility as cancer biomarkers is not well-known. Methods: In this study, we investigate tRFs for correlation to cancer prevalence with specific consideration of translational regulation of oncogenes (OG) and tumor suppressor genes (TSG). tRF read counts were obtained for 499 head and neck squamous cell carcinoma tumor tissue samples and 44 adjacent normal samples. Results: The read counts between both groups were compared to identify tRFs dysregulated in tumor samples, which may be pertinent biomarkers for diagnosis. Ten tRFs were found to be significantly dysregulated in cancer samples. These tRFs were further assessed for correlation to expression of OGs and TSGs using the COSMIC database. Due to the mRNA-degrading nature of tRFs, we analyzed tRF abundance for inverse correlation to gene expression. Four tRFs upregulated in tumor samples showed significant anticorrelation to select TSG expression (ATP2B3, CSMD3, LZTR1, NTHL1, PTPRC), and three tRFs downregulated in tumor samples showed anticorrelation to OG expression (A1CF, MPL, SALL4, TNC). Notably, LeuCAG 5’ tRF was associate with high binding affinity for the TSGs CSMD3 and LZTR1, supporting the likelihood of tRF-mediated degradation. Interestingly, this tRF was inversely correlated with patient survival length. LeuCAG 5’ was also of significantly lesser abundance in patients who experienced complete or partial remission following chemotherapy treatment, further indicating this tRFs’ clinical relevance in HNSCC, potentially as an oncogenic-related agent. Conclusions: Investigation into these tRFs may reveal their potential for use in early diagnosis. High abundance of this tRF may be indicative of oncogenesis. In exploring tRFs’ for their potential as biomarkers of cancer, they may prove useful in allowing earlier diagnosis. Moreover, studying tRFs may provide additional considerations for patient care and treatment.